Endocrine pathophysiology

257

258

Magnocellular neurons Parvocellular hypophyseotropic

neurons

Hypothalamic projection

neurons

259

Hyperpituitarism

● Primary hypothalamic disorders (rare)

● Primary pituitary hyperplasia (rare)

● Functioning carcinomas (extremely rare)

● Functioning adenomas ○ 1. Prolactinomas – see later

○ 2. Somatotroph (GH) adenomas – see later

○ 3. Corticotroph (ACTH) adenomas: Cushing’s disease

○ 4. Gonadotroph (FSH/LH) adenomas ■ Majority produce FSH, some FSH & LH, rarely only LH

■ Occur in middle-aged men & women

■ Symptoms related only to local mass effects, may cause

amenorrhea or galactorrhea, ↓ libido in men

○ 5. Thyrotroph (TSH) adenomas: TSH → hyperthyroidism

○ 6. Pleurihormonal adenomas (GH + PRL)

Prolactin (PRL)

260

During fetal development, prolactin cells

appear to differentiate from GH cells, some

cells maintain the ability to produce both GH

and prolactin

Lactotrophs which make up 40-50% of the

endocrine cells of the anterior pituitary

Prolactin binds to a specific receptor, similar

to GHR (cytokine receptor)

PRL secretion: tonic inhibition by tubero-

hypophyseal dopaminergic pathway

Primary target of PRL: mammary gland

Development during pregnancy

Induces milk protein synthesis

Initiates and maintains lactation

Milk ejection is a reflex process

mediated by oxytocin

261

Hyperprolactinemia

● Hyperprolactinemia is the most common hormone secreting

pituitary tumor

● Causes of hyperprolactinemia ○ 1. Hypothalamic dopamine deficiency

■ Tumors, arterio-venous malformations, inflammatory processes

(sarcoidosis) result in either diminished synthesis or release of

dopamine

■a-methyldopa and reserpine is capable of depleting the central

dopamine stores

○ 2. Defective transport mechanism ■ Section of the pituitary stalk, pituitary or stalk tumors

262

○ 3. Lactotroph insensitivity to dopamine ■ Dopamine-receptor-blocking agents: phenothiazines

(chlorpromazine), butyrophenones (haloperidol), and benzamides

(metoclopramide, sulpiride, and domperidone). They block the

effects of endogenous dopamine → release lactotrophs from their

hypothalamic inhibition → hyperprolactinemia

○ 4. Stimulation of lactotrophs ■ Hypothyroidism with increased TRH production →

hyperprolactinemia

■ Estrogens act directly at the pituitary level, → enhance prolactin

secretion, increase the mitotic activity of lactotrophs.

■ Injury to the chest wall (herpes zooster [HHV-3], post thoracotomy,

piercing)

263

● Consequences of hyperprolactinemia ○ Inhibits pulsatile GnRH secretion → hypogonadism

■ Female: luteal phase is shortened → anovulation, galactorrhea,

amenorrhea, infertility, ↓ libido

■ Male: decreased testosterone synthesis, spermatogenesis and

libido or impotence; rarely galactorrhea & gynecomastia

○ Bitemporal hemianop(s)ia

264

265

The effect prolaction on GnRH secretion and pharmacotherapeutic

options in hyperprolactinemia

GnRH

Hyperprolactinemia

LH

Gonadotroph

Gonads ↓

Hypothalamus

Hypophysis

Dopamin

Pergolide

Cabergoline

Ergot-derived dopamine agonists

266

● Treatment of hyperprolactinemia ○ Dopamine agonists for GH or prolactin hyper secretion

■ Most useful when GH and prolactin secretion also is elevated

■ Paradoxical inhibitory effect on GH secretion: Somatroph

adenomas express receptor characteristics of lactotrophs

■ Given orally; adverse effects: nausea, vomiting, dizziness, postural

hypotension

○ Transsphenoidal microsurgery ■ Microadenomas - 85% long term remission

■ Macroadenomas – outcome less satisfactory

267

An almost complete bitemporal hemianop(s)ia (pre-therapy), which had almost disappeared after 1

year of treatment with bromocriptine, returned on cessation of therapy and began to subside after

reinstitution of bromocriptine.

The black periphery indicates a normal visual field for comparison.

268

Hypopituitarism ● Subnormal basal or stimulated secretion of one or more pituitary

hormones ○ > 50% of secretory cells – detectable deficiency, > 80% lost for severe

basal loss

○ In pituitary failure a common sequence of hormone loss is GH >

FSH/LH > TSH > ACTH > PRL

○ Prolactin is often increased from compression of the pituitary stalk and

interruption of dopamine inhibition

● Loss of pituitary hormones generally results in milder symptoms than

when the target gland itself is inadequate ○ Tendency for residual function of target glands to continue, yielding

basal serum levels that overlap with normal persons

○ ! Need to perform dynamic tests of many pituitary hormones to assess

maximal responses !

269

● Hypopituitarism is caused by hypothalamic or pituitary lesions ○ Hypothalamic lesions – anterior and posterior lobe deficiencies

■ Craniopharyngioma, gliomas & teratomas; metastatic carcinoma,

infections, infiltrative diseases: sarcoidosis, tuberculosis, mycoses,

hemochromatosis

○ Pituitary lesions (anterior lobe deficiencies) ■ Adenomas (10-15% of all brain tumors): majority are benign and

remain within the sella turcica (microadenoma) □ Nonsecretory adenomas

□ Prolactin-secreting adenomas – most common

■ Sheehan’s syndrome (see later), irradiation or destruction/removal

of 75% of the gland

■ Rare: metastatic carcinoma, inflammatory disorders, infections,

genetic defects (Pit-1 {pituitary-specific transcription factor} gene)

270

Rathke’s pouch

271

Clinical forms of hypopituitarism

● 1. Panhypopituitarism or Simmonds’ disease due to destruction

of pituitary tissue by tumor or infarction ○ In children → dwarfism & infantilism (retarded physical & sexual

development)

○ In adults → hypogonadism, hypothyroidism & hypoadrenalism

● 2. Sheehan’s syndrome ○ Ischemic necrosis of the anterior pituitary due to postpartum

hemorrhage and/or shock

○ Predisposing factors ■ Anterior pituitary doubles in size during pregnancy, low pressure

portal system unable to ↑ blood supply

■ Abrupt onset of hypotension (eg bleeding) → hypoperfusion →

infarction

272

○ Early symptoms: breast atrophy and failure of lactation, within

first 7 days postpartum; later amenorrhea

○ Low TSH: fatigue, slow speech, slow movements, cold

intolerance, dry skin, constipation.

○ Low ACTH: fatigue, hypotension, poor tolerance of stress and

infection, hypoglycemia, loss of pubic and auxiliary hair,

decreased body hair, decreased pigment in skin, waxy skin

○ Posterior lobe: usually is not affected

● 3. Isolated hormone deficiencies

○ GnRH deficiency

■ Acquired in hyperprolactinemia and in hyper-cortisolemia because

PRL and cortisol decrease GnRH gene expression

■ Acute and chronic illness, and poor nutrition → GnRH deficiency

■ Kallmann syndrome

273

Kallmann’s syndrome

Isolated hypogonadotropic hypogonadism with anosmia (inability to smell) defect in KAL gene (X-

linked form)

Dominant, recessive and X-linked recessive/dominant forms are known

Mutation in a neural cell adhesion protein (anosmin encoded by KAL) which guides axon growth

and allows GnRH neurons to migrate from their site of origin in the cribriform plate to the anterior

hypothalamus

Because GnRH neurons are not in their appropriate anatomical location, axons to the anterior

pituitary do not develop; defective synthesis/release GnRH (FSH, LH, testosterone ↓); Anosmia,

microphallus

Migration of GnRH-secreting neurons (color)

from the nose anlage into the hypothalamic

portion of the brain. This migration does not

occur in Kallmann syndrome.

274

○ FSH/LH deficiency ■ Prepubertal hormone deficiency

□ Impaired development of secondary sex characteristics, primary

amenorrhea (♀)

□ Eunuchoid habitus due to delayed epiphyseal closure (arm span: 5

cm > height)

■ Adult women: amenorrhea, infertility, hot flashes, decreased libido

and low estradiol

■ Adult men: hypogonadism and/or infertility, hot flashes, testicular

atrophy, low testosterone □ Fertile eunuch (LH deficiency)

○ TSH deficiency: see secondary hypothyroidism

○ ACTH deficiency see white Addison’s

○ PRL deficiency ■ Congenital PRL deficiency is a very rare disorder, occurs together

with GH and TSH deficiency due to mutations of Pit-1

■ Inability to lactate (as in Sheehan’s)

275

276

Growth-hormone excess

● Childhood – gigantism

● Adults – acromegaly (rare, 3-4 new cases per million) ○ Progressive enlargement of head, face, hands, feet, thorax; heat

intolerance, sweating, fatigue, lethargy

○ Levels of IGF-1 are greatly increased in acromegalics but IGF-2

levels are not.

○ Etiology ■ 98%: benign GH-producing pituitary tumor

■ 2%: Ectopic GHRH secretion □ Small cell lung cancer, bronchial or intestinal carcinoid tumors,

pancreatic islet cell tumor, pheochromocytoma

277

● Complications ○ Local – due to mass effect (marcoadenoma)

○ Abnormal glucose tolerance (DM – 1/3) – GH is insulin antagonist

○ ↑ se triglyceride

○ Cardiovascular complications ■ Left or bi ventricular hypertrophy → heart failure, arrhythmia

■ Hypertension: due to Na retention, ↑ sympathetic activity

○ Obstructive sleep apnea

○ Colorectal cancer

● Diagnosis ○ Abnormal net GH secretion over time & non-suppressible GH

secretion ■ 24 hour GH profile (night-time GH levels)

■ Elevated IGF-1 and IGFBP-3 (most important binding protein of

IGF-1)

278

Disorders of growth in childhood

● I. Dwarfism due to growth hormone deficiency

○ 1. Genetic

■ Transcription factor abnormalities

□ Multiple pituitary hormone deficiency (Pit-1, PROP-1 [prophet of Pit1])

■ GHRH receptor abnormalities

■ Defects of GH gene – structural growth hormone mutations

■ Bioinactive GH syndrome – normal to high GH level, low IGF-1

○ 2. Congenital/developmental abnormalities

■ Structural brain development disorders (septo-optic dysplasia, agenesis

of corpus callosum); midline facial defects (cleft lip/palate)

○ 3. Craniopharyngioma (tumor of Rathke’s pouch) → compression

signs: increased intracranial pressure and visual field defects

○ 4. Cranial irradiation (leukemia)

■ 50% chance of deficiency in 5 yrs, 100 % in 10 yrs

279

280

○ 5. Psychosocial dwarfism (stress dwarfism) ■ Growth problems in kids over 3 yrs

■ Possible mechanisms □ Hypophyseal insensitivity to GHRH

□ Cells become insensitive to GH and IGF-1

□ Too much somatostatin or the pituitary is too sensitive to somatostatin

□ Sympathetic system over activity: blocks GH secretion

□ Glucocorticoids ↑: block GH secretion; decrease sensitivity to GH;

decrease synthesis of new proteins and DNA ♦ Hormone levels 2 to 3 ↑ normal – disrupt growth, major stressors

increase hormone levels up to 10 ↑ normal

● Children who are GH deficient have short stature of varying

degree with normal proportions (proportionate dwarfism) but may

appear younger than their age ○ Increased insulin sensitivity

■ Hypoglycemia (mostly infants and small children)

○ Decreased muscle mass, increased fat mass

● II. Etiology of growth hormone insensitivity ○ Laron syndrome: Normal/high se GH level but reduced circulating

levels of IGF-1 due to a defect in the GH receptor ■ Treatment: biosynthetic IGF-1 before puberty

281

Laron syndrome

•Dwarfism

•Prominent forehead, depressed

nasal bridge, underdeveloped

mandibule

•Truncal obesity

•Hypoglycemic episodes

•Resistance to DM and cancer

•Intellectual retardation

282

Human recombinant GH (in GH

deficiency)

Human recombinant IGF-1 ( in GH

insensitivity syndrome)

Short stature

(dwarfism) is defined

as height less than 2

standard deviations

below the mean,

which is near the

third percentile.

Thus, 3-5% of all

children are

considered short.

283

● III. Growth failure due to other conditions ○ 1. Familial short stature – not a true growth failure

■ Parents with short stature. These children have a normal growth

velocity and puberty and finish their growth with a short adult

height.

○ 2. Constitutional delay in growth and maturation – delayed

puberty ■ A period of slow growth velocity occurs during the first year of life,

and, just before the onset of puberty (normal adult height)

■ Children with constitutional delay may have a family history of the

same

○ 3. Malnutrition – the most common cause of growth failure

worldwide

284

○ 4. Chronic or systemic disorders ■ Nervous system: microcephaly

■ Circulatory system: cyanotic heart diseases

■ Gastrointestinal system: Gluten sensitive enteropathy, ulcerative

colitis, or Crohn’s disease

■ Liver, chronic renal failure: renal tubular acidosis

■ Lung: cystic fibrosis

■ Connective tissue: dermatomyositis

○ 5. Chromosomal abnormalities ■ Turner syndrome (45,X) and Down syndrome (trisomy 21)

285

○ 6. Other (non-chromosomal) syndromes ■ Noonan syndrome: Short stature, heart disease (pulmonary

stenosis), unusual facies, mental retardation, bleeding diathesis;

neurological, genitourinary, lymphatic, eye, and skin findings may

be present to varying degrees (should be differentiated from

Turner’s syndrome) □ Abnormal Ras-MAP kinase signalization

■ Prader-Willi syndrome: obesity, hypotonia, mental retardation,

short stature, hypogonadotropic hypogonadism, strabismus, and

small hands and feet

286

○ 7. Target tissue defects ■ Intrauterine growth retardation

□ Fetal alcohol syndrome and placental insufficiency syndromes.

■ Bone and cartilage disorders - due to mutations of the fibroblast

growth factor receptor 3 □ Achondroplasia – autosomal dominant disorder

♦ Decreased endochondral ossification, inhibited proliferation of

chondrocytes in growth plate cartilage, decreased cellular hypertrophy,

and decreased cartilage matrix production

♦ Growth retardation, disproportionably short arms and legs, lumbar

lordosis. The head is large, the forehead is prominent.

□ Hypochondroplasia – disproportion is subtle

287

288

○ 8. Endocrine causes ■ GH deficiency and GH insensitivity (IGF-1 deficiency) – see earlier

■ Thyroid hormone deficiency (hypothyroidism) □ Thyroid hormone is necessary for normal growth (thyroid hormone

levels should be measured in all children with slow growth)

■ Parathormone resistance: Albright hereditary osteodystrophy

■ Glucocorticoid excess (Cushing’s syndrome, Cushing’s disease) □ Children with glucocorticoid excess almost always have growth

failure

■ Androgen excess □ Due to exogenous androgen, precocious puberty, and congenital

adrenal hyperplasia

□ The growth velocity increases in the short term, but epiphyseal fusion

occurs early, resulting in a short adult height

289

Adult GH deficiency

● Adult-onset pituitary/hypothalamic disease, craniopharyngioma, surgery,

irradiation therapy, or trauma

● Features of GH deficiency in adults ○ Increased fat mass (apple type obesity) and reduced lean body mass

○ Decreased insulin sensitivity, impaired glucose tolerance

○ Accelerated atherosclerosis (↑LDL, ↓HDL cholesterol)

○ Impaired cardiac function

○ Decreased bone density

○ Mood changes

○ Hypopituitarism is associated with premature mortality (mainly in females)

● Replacement therapy in GH-deficient adults alters body composition and

energy metabolism through its lipolytic, protein anabolic and antinatriuretic

actions, resulting in decreased fat mass, increased fat-free mass Na

retention and increased energy expenditure

290

291

Iodine

● Deficiency ○ Moderate iodine deficiency – euthyreoid goiter

○ Severe iodine deficiency ■ Endemic myxedema in adults; endemic cretinism in infants

● Toxicity ○ Increased iodine uptake – inhibition of thyroid hormone synthesis

(Wolff-Chaikoff effect)

○ Hyperthyroidism („Jod-Basedow” phenomenon = iodine-induced

hyperthyroidism)

○ Very high doses of iodide ■ A brassy taste, increased salivation, and acneiform skin lesions

292

● Wolff-Chaikoff effect ○ Increasing doses of I- increase hormone synthesis initially

○ Higher doses cause cessation of hormone formation.

○ This effect is countered by the iodide leak from normal thyroid

tissue and the hormone synthesis resumes.

○ Patients with autoimmune thyroiditis may fail to adapt and

become hypothyroid (suppressive effect of iodide persist)

● Jod-Basedow effect ○ Aberration of the Wolff-Chaikoff effect

○ Excessive iodine loads induce hyperthyroidism

○ Observed in several disease processes ■ Basedow-Graves’ disease

■ Multinodular goiter

293

Well Sick Recovery Well

Reference range

T3 totalT4

freeT4

Mortality↑

reverseT3

Sick euthyroid syndrome

•Occurs in critically ill patients (sepsis, MI), but may occur with DM, malnutrition, iodine

loads, or medications (amiodarone [rich in I], glucocorticoids)

•Euthyroid condition (TSH normal) but thyroid hormone (T3, T4) level is low. Inactivation of

5’-deiodinase, resulting in conversion of free T4 to reverseT3.

•Pathomechanism: still at large, inflammatory cytokines (eg sepsis)

•Treatment: Avoid above medications, treat primary illness; T3, T4 not helpful

294

Thyrotoxicosis

● With thyroid hyperfunction (Hyperthyroidism – sustained

hormone overproduction) ○ Excess production of TSH: hypophyseal tumor

○ Abnormal thyroid stimulation ■ Basedow-Graves’ disease (see autoimmune diseases),

throphoblast tumor (chorionic gonadotophin-induced)

○ Intrinsic thyroid autonomy ■ Toxic multinodular goiter

■ Toxic adenoma □ Activating mutations of the TSH-R

295

● Without thyroid hyperfunction (transient hormone excess) ○ Disorders of hormone storage

■ Subacute thyroiditis or chronic thyroiditis with transient

thyrotoxicosis

○ Extrathyroid source of hormone ■ Thyrotoxicosis factitia (overdose with thyroid hormone products)

■ Ectopic thyroid tissue □ Struma ovarii (ovarian teratoma), functioning follicular thyroid

carcinoma

296

Hypothyroidism

● A hypometabolic state caused by deficiency of T3 & T4

● 1. Primary hypothyroidism – thyroid gland failure (95%) ○ Thyroid gland dysfunction

■ Congenital developmental disturbances

■ Radioactive iodine therapy or subtotal thyreoidectomy in Basedow-

Graves’ disease

○ Congenital biochemical disturbances (hormone synthesis)

○ Cretinism ■ Sporadic cretinism: congenital –thyroid dysgenesis, inherited

defects in thyroid hormone synthesis, inherited peripheral tissue

resistance to thyroid hormone

■ Endemic cretinism: due to dietary iodine deficiency – in certain

geographical regions; Central Africa, Andes, Himalaya □ Severe mental retardation, short stature, coarse facial features,

protruding tongue, possible deafness

297

○ Myxedema: adult hypothyreosis ■ Hashimoto’s thyreoiditis

■ Subacute thryroiditis (DeQuervain’s, granulomatous) □ Acute viral infection of thyroid gland: Presents with viral prodrome,

thyroid tenderness, and hyperthyroid symptoms

■ Surgical ablation

■ Iodine deficiency

■ Drugs (lithium, thio-uracyl)

■ Idiopathic primary hypothyroidism

■ Hypothalamic and hypophyseal disturbances

● 2. Secondary – pituitary ablation, failure or necrosis ■ TRH normal & low free thyroxin. Note that the TSH cannot be used

as a screening test for TSH deficiency!

■ Hypothyroidism is less severe than in primary hypothyroidism

● 3. Tertiary – hypothalamic failure (rare) ○ No TRH and TSH

298

Pathogenesis of Hashimoto’s thyroiditis

● Familial predisposition, associated with HLA-DR3 or HLA-DR5

● Defective function of thyroid-specific suppressor T cells →

emergence of helper T cells reactive with thyroid antigens

● Helper T cells stimulate B cells to secrete antithyroid antibodies,

directed against: thyroid peroxidase (TPO), TSH-receptors,

iodine transporter, & thyroglobulin (TBG) etc.

● Thyroid injury is mediated by complement fixing cytotoxic

antibodies, ADCC & CD8+ cytotoxic cells

● Ninety % of gland is destroyed before hypothyroidism develop

299

Hashimoto’s thyroiditis

300

24 yrs. old athyreotid cretin

Myxedema (hypothyroidism in adults)

Fatigue, lethargy, slowed speech, mental

sluggishness, cold intolerance, weight gain,

constipation, ↓sweating, bradycardia,

accumulation of ECM substances

(glycosaminoglycans), coarsening of facial

features, nonpitting edema

301

Myxedema: showing periorbital bags under eyes

Loss of lateral eyebrow; Anne’s sign

Swollen inner eyelid: Julesz’ sign After treatment

Myxedema

302

Goiter (enlargement of the thyroid)

↓ thyroid hormone synthesis

→ TRH & TSH↑ →

hyperplasia & hypertrophy of

follicular cells → gross

enlargement

Functionally: decreased,

normal or hyperfunctional

History of goiters

Aristotle: individuals with goiter are spirited and rash

Galen: tumor of larynx and pharynx

Aetius of Amida: bronchocele that is a rupture of larynx

Paul of Aegina: two varieties: the steatomatous and the aneurysmatic

Emperor Leon VI the Wise: the man, who has a great walnut around the

neck, and has bulging eyes, is considered as healthy

Diffuse non-toxic (simple) goiter

● Endemic goiter ○ Dietary deficiency of iodide

○ Goitrogens (e.g. cabbage,

cauliflower, turnips, cassava root)

manioc: linnamarin thiocyanate:

blocs uptake of iodine at the

thyroid, competitive inhibition

○ Usually results in cretinism

● Sporadic goiter ○ Goitrogens

○ Hereditary defect in thyroid

hormone synthesis

● Clinical: most patients are

euthyroid

Multinodular goiter

● Nodular enlargement, derived

from diffuse goiter (both

monoclonal & polyclonal

nodules (adenomatous goiter)

● Clinical ○ Most patients are euthyroid

○ Mass effects: compression of

trachea, vessels & nerves, &

dysphagia

○ Hyperthyroidism (toxic

multinodular goiter) ■ Due to a hyperfunctioning nodule

but not accompanied by

opthalmopathy or dermopathy

303

304

305

hypoglycemia, hypovolemia, fever

Vasopressin

Pro-inflammatory

cytokines

Adrenal gland

↑ gluconeogenesis and ↓ uptake of glucose by fat & muscle

↓ protein synthesis, ↑ protein degradation

↑ vascular tone, some mineralocorticoid activity, anti-

inflammatory & immunosuppressive effects

306

Adrenal gland

Kidney

Adrenal cortex

Adrenal medulla

Adrenal cortex Adrenal medulla Connective tissue

capsule

Synthesis of aldosterone –

C-18-OH present only here

Androgens (mainly dehydroepinandrosterone [DHEA])

•Converted to estrogens in females and promote libido and the

only source of androgens after menopause

•Excess testosterone in females: defemenization &

virilization; (hirsutism, acne, amenorrhea, clitoral

enlargement, atrophy of the breasts & uterus,

deepening of the voice & frontal balding).

•In boys leads to precocious puberty. ACTH dependent

ACTH acts on

melanocortin-2 receptors

[MC2-R]

Glucocorticoids

Zona

reticularis

Zona

fasciculata

Zona

glomerulosa

An

dro

gen

s

307

Angiotensinogen

Angiotensin I (1-10) Angiotensin (1-9)

Angiotensin II (1-8) Angiotensin (1-7)

Angiotensin (2-8)

Angiotensin (3-8)

Renin Cathepsin

t-PA

ACE

(lung)

AT1 AT2

PRR

AT2

AT1

AT4

Mas

Inactive fragments

Bradykinin Chymase

ACE-2

ACE-2

ACE NEP

APA

APN/APB NFB activation

Proinflammatory factors:

TNF-a, MCP-1, IL-6, ICAM-1

PAI-1

Vasodilatation

Anti remodeling

Anti fibrotic

Anti thrombotic

Contractility

Hypertrophy

Fibrosis

Apoptosis

Vasoconstriction

Antidiuresis/antinatriuresis

Cell growth and proliferation

Aldosterone and vasopressin

release

Oxidative stress

Vasodilatation

Diuresis/natriuresis

Anti-proliferation

Bradykinin and NO production

Prorenin

Diseases of the adrenal cortex

Hyperadrenalism

● Cushing’s syndrome

● Hyperaldosteronism /

aldosteronism ○ Primary or secondary

● Adrenogenital syndromes

(congenital adrenal hyperplasia)

Hypoadrenalism

● Acute „Addisonian or adrenal

crisis” (e.g. Waterhouse-

Friderichsen syndrome)

● Chronic ○ Primary (due to adrenal cortical

insufficiency, e.g. Addison’s

disease)

○ Secondary (due to ACTH

deficiency)

○ Tertiary (rarely – due to

hypothalamic CRH deficiency)

308

309

Cushing’s syndrome

● Overproduction of glucocorticoids ○ ACTH-dependent forms

■ Primary bilateral macronodular adrenal hyperplasia □ Increased intra-adrenal ACTH release stimulates MC2-Rs to produce

cortisol by paracrine manner

■ Secondary bilateral macronodular adrenal hyperplasia □ Cushing’s disease : pituitary hypersecretion of ACTH. Nelson’s

syndrome: after adrenalectomy (due to inoperable pituitary tumor)

ACTH-dependent hyperpigmentation of the skin ( MSH)

□ Ectopic production of ACTH or CRH by bronchogenic small cell

carcinoma

○ Non-ACTH-dependent forms ■ Autonomous hypersecretion of cortisol by an adrenal adenoma,

carcinoma

■ Exogenous/iatrogenic: high dose cortisone therapy

310

Mood changes: irritability,

depression, psychosis

Endocrine changes:

↓LH,FSH

↓TSH

↓GH

Glaucoma

Peptic ulcer

Cardiovascular & renal: Salt & water

retention, hypertension, K loss Fat distribution: Obese, visceral

obesity, centripetal fat distribution:

supraclavicular fat (buffalo hump),

facies lunata (moon face)

Carbohydrate/lipid metabolism

•Glucogenolysis & gluconeogenesis ↑

•Free fatty acid (FFA) ↑

•Impaired glucose tolerance, insulin

resistance, diabetes mellitus

Skin/muscle/connective tissue:

•Loss of muscle, proximal myopathy,

•Plethora, striae rubrae distensae, increased capillary fragility

•Short stature

Osteopenia/osteoporosis

Blood & immune function

•Lymphocyte and eosinophil # decreased

•Anti-inflammatory and immuno

suppressive effect

•Neutrophil and total WBC increased

•RBC and HT increased

Changes in sexual function

•Androgen effect in females

(masculinisation)

•Loss of libido

•Menstruation abnormalities

311

312

Primary aldosteronism / hyperaldosteronism

● Excessive secretion of aldosterone independent of renin-angiotensin

system (low renin) with hypervolemia, hypertension, hypokalemia (in

30% of patients normal serum K) and metabolic alkalosis

● Forms

○ 1. Conn syndrome – aldosterone-secreting solitary adenoma

○ 2. Idiopathic aldosteronism – diffuse bilateral hyperplasia

○ 3. Rare subtypes

■ Familial hyperaldosteronism type I or glucocorticoid-suppressible

hypertension

□ Hybrid cells produce both cortisol & aldosterone, ACTH-dependent

aldosterone production, suppressible by administration of dexamethasone

■ Unilateral hyperplasia

■ Aldosterone-producing cortical carcinoma

313

Glucocorticoid-remediable hyperaldosteronism (primary

hyperaldosteronism autosomal dominant form)

Unequal crossing over in the promoter region of 11ß-hydroxylase

Aldosterone secretion is regulated by ACTH

314

Secondary aldosteronism / hyperaldosteronism

● A diverse group of disorders characterized by physiologic

activation of the renin-angiotensin-aldosterone axis to maintain

serum Na concentrations or fluid volume. ○ In the presence of normal renal function, it may lead to

hypokalemia

● 1. Presence of hypertension ○ Reninism

○ Decreased kidney perfusion (renovascular, parenchymal

hypertension)

315

● 2. Absence of hypertension – usually with edema formation ○ Homeostatic mechanism to maintain Na or circulatory volume or

to reduce plasma K

○ Congestive heart failure, and hypoalbuminemia due to liver or

renal disease or nephrotic syndrome

○ Diarrhea, excessive sweating, low cardiac output states

● 3. No high blood pressure and no edema ○ Bartter’s, Gitelman’s syndrome

■ Autosomal recessive disease, Kidney is unable to keep Na, Cl, K

(thick ascending segment)

316

Adrenogenital syndromes

● Adrenogenital syndromes: ambiguous genitalia & virilism in

girls, and precocious puberty in boys

● Causes ○ 1. Androgen-secreting adrenal cortical neoplasms

○ 2. Congenital adrenal hyperplasia (CAH): corticosteroid

biosynthetic defect ■ C-21-hydroxylase deficiency (90% of CAH cases; autosomal

recessive) □ ↓cortisol → feedback inhibition of ACTH ↓ → ↑ ACTH levels →

bilateral adrenocortical hyperplasia

□ Aldosterone synthesis is blocked → salt wasting adrenogenitalism

(se Na+ ↓, ↑ K+, hypovolemia)

□ ↑ production of androgens

317

■ C-11 ß-hydroxylase deficiency (Israel, Moroccan descents) □ Hypergonadism: masculinization of female newborn, precocious

puberty in boys

□ Hypertension (ACTH-mediated DOC accumulation), renin↓,

aldosterone↓, hypokalemia, metabolic alkalosis

□ Other forms: salt-wasting, non-classical (see clinical studies)

■ C-17 α-hydroxylase deficiency (~150 cases) □ Hypertension (ACTH-mediated DOC accumulation), hypogonadism,

(sexual infantilism) renin↓, aldosterone↓, hypokalemia, metabolic

alkalosis

318

Estradiol

* DOC

*

319

Acute adrenocortical insufficiency „Addisonian crisis”

● Acute adrenocortical insufficiency is sudden withdrawal of

corticosteroids in cases of long-term steroid therapy, or

destruction of adrenals by massive hemorrhage

● Waterhouse-Friderichsen syndrome: overwhelming

meningococcal septicemia ○ Disseminated intravascular coagulation (DIC) with widespread

purpura, rapidly progressive hypotension → shock, massive

bilateral adrenal hemorrhage → acute adrenocortical

insufficiency

320

Primary chronic adrenocortical insufficiency

(Addison’s disease)

● Due to autoimmune adrenalitis, tuberculosis, metastatic

cancers

● Destruction of 90% of the cortex → decreased cortisol and

aldosterone production, ○ Cortisol deficiency with feed-back elevation of ACTH and MSH

→ hyperpigmentation of skin (♀ bra; ♂ belt)

○ Mineralocorticoid deficiency → ECF volume contraction → GFR

reduction ■ Enhanced proximal salt absorption (glomerulotubular feedback)

■ Volume-mediated, non-osmotic ADH release ↑

■ ↑ K+, ↓ Na+, ↓ BP, weakness, anorexia, hypoglycemia

Secondary chronic adrenocortical insufficiency (white

Addison’s)

● ACTH deficiency due to hypothalamic/pituitary

lesion → bilateral adrenal cortical atrophy,

sparing the zona glomerulosa, which is primarily

regulated by renin and angiotensin ○ ACTH deficiency leads to cortisol and adrenal

androgen deficiency, but aldosterone secretion is

preserved

● Common symptoms are fatigue, muscle

weakness, anorexia and weight loss, fair skin

pigmentation and hair. Hyponatremia and

hypoglycemia may be present, but severe

dehydration and hyperkalemia do not occur 321

322

Adrenal medulla

● Composed of specialized neuroendocrine (chromaffin) cells, and is the

major source of catecholamines: epinephrine, norepinephrine & dopamine

○ Chromaffin cells secrete catecholamines in response to signals from

preganglionic sympathetic nerve fibers and variety of bioactive amines

and peptides, such as: histamine, serotonin, & neuropeptide hormones

323

Paraganglial tumors: pheochromocytoma &

paraganglioma

● Highly vascular, catecholamine-secreting, mostly benign tumors

(10% are malignant); pheochromocytomas are involving one or

both adrenal glands. Paragangliomas are derived from thoracic

and abdominal paraganglia along the sympathetic chain

● Clinical appearance of paraganglial tumors ○ Sporadic

○ Inherited ■ Mutation of one of at least 12 genes from wide range of functional

classes

■ Paraganglial tumors carry the highest degree of heritability in

human tumors

■ Components of multiple endocrine neoplasia-2 (MEN-2)

324

parasympathetic sympathetic

Catecolamine secretion No catecolamine secretion

325

● Release of excess amounts of catecholamines → paroxysmal

or sustained hypertension (blood pressure fluctuations and

predisposition to orthostatic hypotension is detectable),

tachycardia, arrhythmias, tremors, sweating, sense of

apprehension, attacks can be fatal ○ Paroxysms (< 50% of patients) are precipitated by exercise,

bending over, urination, defecation, induction of anesthesia,

infusion of intravenous contrast media, smoking

● Diagnosis ○ Serum & collected urine (24 hour) for catecholamines,

metanephrine, normetanephrine & vanillylmandelic acid (VMA)

determination

○ Free metanephrine has the highest diagnostic sensitivity and

specificity

326

327

Female reproductive disorders – menstrual disorders

● Polymenorrhea – intervals between uterine bleeding < 24 days

● Oligomenorrhea – intervals between uterine bleeding > 35 days

● Amenorrhea – absence of menstruation ○ Primary amenorrhea

■ Menarche never occurred: usually due to genetic disorders or

congenital defects

○ Secondary amenorrhea ■ Absence of menstruation for a time equivalent to 3 or more cycles

or 6 months in women who have previously menstruated

■ May result from impediment in hypothalamic-pituitary axis or from

dramatic weight loss or other physiologic conditions

● Hypermenorrhea – regular intervals (24-35 days) but excessive

flow (over 80ml [normal: 30 ml] and/or duration (normal: 4-6

days) of bleeding

328

● Hypomenorrhea – diminution of flow and/or duration of bleeding

● Dysmenorrhea – painful menstruation ○ Primary dysmenorrhea

■ Results from periodic uterine contractions due to excessive

prostaglandin F in secretory endometrium.

■ Prostaglandins may also cause headache, syncope and GI

complaints (diarrhea)

■ Increase in myometrial contractions and constricting endometrial

vessels, ischemia, pain

○ Secondary dysmenorrhea results from pelvic disorders:

endometriosis, uterine polyps, tumors, pelvic inflammatory

disorders or congenital anomalies

329

● Uterine bleeding in response to steroid hormones ○ Estrogen withdrawal bleeding

■ Bleeding due to acute cessation of estrogen support (in the

absence of progesterone) to the endometrium

■ Bilateral oophorectomy, radiation of mature follicles

○ Estrogen breakthrough bleeding (unpredictable) ■ Chronic exposure to estrogen stimulates continuous endometrial

growth (e.g extragonadal production of estrogen in PCOS), but

after a time the amount of estrogen is insufficient to support

endometrial function → bleeding

○ Progesterone withdrawal bleeding (predictable) ■ Physiologic: bleeding after ovulation (in the absence pregnancy)

■ Discontinuation of progesteron or progestins (synthetic form)

○ Progesterone breakthrough bleeding (pharmacologic

phenomenon) ■ Oral contraceptives – Depo-Provera: low-dose estrogen, high

dose, long acting progestin

330

● Causes of irregular uterine bleeding ○ Complications of pregnancy

■ Ectopic pregnancy, miscarriage

○ Anovulations ■ Physiologic: pubertal and postmenopausal anovulation

■ Chronic anovulations

○ Anatomic defects affecting the uterus ■ Leiomyomas, polyps, endometriosis

○ Coagulation defects (as hypermenorrhea) ■ Von Willebrand’s disease etc

○ Extrauterine, genital bleeding (may mimic uterine bleeding) ■ Genital trauma, foreign body

331

Disorders of the female reproductive system

● 1. Chronic anovulation ○ Estrogen deficiency (with osteopenia and osteoporosis)

■ Hypothalamic anovulation

■ Hyperprolactinemia-galactorrhea (see earlier)

■ Premature ovarian failure in reproductive years

○ Androgen excess (risk of endometrial carcinoma etc) ■ Polycystic ovarian syndrome

● 2. Hormone-dependent benign gynecological disease:

endometriosis (see gynecology)

● 3. Menopause (see gynecology)

332

Chronic anovulation due to estrogen deficiency

● Functional hypothalamic anovulation: aberrant but reversible

defect in the neuroendocrine regulatory pathway; may be

associated with excessive exercise (CRH and ß-endorphins ↑),

dieting (anorexia, bulimia) or emotional distress ○ Slowdown in the frequency of LHRH secretion

■ Changes in dopaminergic activity (↓↑)

■ Increased endogenous opioid peptides

■ Chronic activation of the hypothalamo-pituitary axis □ Can be prevented by administration of CRH and opiate antagonist

○ Low estrogen and gonadotropins levels

○ Secondary amenorrhea

333

● Premature ovarian failure in reproductive years: depletion of

follicles before age of 40 ○ In most cases the etiology is not clear

■ Perhaps genetic cause to cause ovarian follicles disappear at a

faster rate □ Mutations of FSH, LH receptors

□ Galactosemia (accumulation of galactose-1-phosphate at toxic level

due to lack of galactose-1 phosphate uridyltransferase)

□ 45X, 47XXY {mosaicism}

■ Autoimmune process (polyendocrine syndromes: hypothyroidism,

hypoadrenalism, hypoparathyroidism, DM or SLE)

■ Chemotherapy, radiation

○ Amenorrhea, oligomenorrhea, infertility with usually high FSH &

LH

Chronic anovulation due to androgen excess

334

Testosterone is directly secreted by the ovaries to the blood

Estradiol

Estrogen dependent

Malignancies of breast

& endometrium

Dihydrotestosterone

Androgen dependent

Hirsutism & virilization

Causes of androgen excess

Adrenal – overproduction of testosterone precursors

(DHEAS, DHEA, androstendione)

Cushing’s syndrome

Glucocorticoid resistance

Virilizing adrenal tumor

Other Idiopathic hirsutism, hyperprolactinemia etc

Ovarian

Polycystic ovarian syndrome (PCOS)

Hyperthecosis (severe variant of PCOS)

Ovarian tumor (Sertoli-Leydig cell tumor)

Testosterone or androstendione ↑

A – Androstendione E1 – Estrone T – Testosterone

Skin

Fat

Aromatase

17ßHSD

17ßHSD

5-a reductase

Hirsutism: presence of terminal

hair: cheek, upper lip, chin, middle

chest hair; male escutcheon: inner

thighs, intergluteal area

Idiopathic hirsutism: female with

Mediterranean origin (cutaneous

5α-reductase activity ↑)

Virilization: thickening of voice,

clitoromegaly, temporal balding,

decrease in breast size, increase in

muscle mass

335

Polycystic ovarian syndrome (PCOS)

● The most common endocrine disorder affecting ~6% of women

of reproductive age with uncertain origin & elusive

pathophysiology. PCOS risk is significantly increased with

positive family history for anovulation and androgen excess

(polygenic inheritance ?) ○ Antonio Vallisneri (1721): “Young peasant woman, married,

moderately plump, infertile, with ovaries larger than normal, like

doves’ eggs, lumpy, shiny and whitish”

○ Stein-Leventhal syndrome (1935)

● Major components of the syndrome ○ 1. Clinical: polycystic ovaries,menstrual abnormalities,

anovulatory infertilities, repeated miscarriages, hirsutism, acne,

alopecia

336

Estradiol ↑ LH ↓ FSH

Obesity

Inzulin resistance

Dyslipidemia

Hyperinsulinemia

Low circulating progesterone level

↑ Androgens

Central opiate tone ↓

↓

Increased GnRH

pulsatile activity

337

○ 2. Endocrine: elevated androgens, luteinizing hormone,

estrogen and prolactin ■ Exaggerated GnRH pulse frequency and amplitude in the

hypothalamus → LH ↑ → LH-dependent androgen synthesis ↑ in

thecal cells in the ovary w clinical sign of hyperandrogenism □ Theca cells are more effective in PCOS to convert androgen

precursors to testosterone, than normal cells

■ Adrenal androgen production is also enhanced

■ High estrogen levels can cause suppression of FSH and a relative

increase in LH □ Unopposed estrogen action → well-rugated vagina

■ Low FSH level is not enough to mediate androgen → estrogen

metabolism in folliculi → anovulation □ Exclusion of other causes of anovulation: thyroid disorders,

hyperprolactinemia, Cushing’s syndrome, late onset congenital

adrenal hyperplasia, ovarian and adrenal tumors

○ 3. Metabolic: hyperinsulinemia, insulin resistance, obesity,

impaired glucose tolerance, type 2 DM, lipid abnormalities ■ Hyperinsulinemia

□ Stimulates hypothalamic LH secretion

□ Stimulates theca cells androgen production

□ Decreased production of testosterone-binding globulin and IGF-

binding protein 1 in the liver → circulating androgen hormone level ↑

□ Enhanced adrenal androgen production (sensitivity to ACTH ↑)

■ PCOS „diabetes of bearded woman” – 1921 □ 30% of women with PCOS have IGT & 8-10% will have undiagnosed

Type 2 DM

338

339

Hormonal regulation in males

340

341

Disorders of the male reproductive tract

● I. Abnormalities of androgen metabolism and testicular function ○ Fetal life ○ Neonatal life ○ Puberty ○ Adult life

■ Infertility with abnormal virilization (hypothalamic, pituitary and testicular diseases)

■ Infertility with normal virilization (hypothalamic, pituitary, testicular and sperm transport diseases)

○ Old age: disorders of the prostate gland (see urology) ● II. Abnormalities in estrogen metabolism

○ Estrogen excess: gynecomastia ○ Impairment of estrogen formation and action: aromatase

deficiency; estrogen receptor a deficiency

342

Abnormalities of androgen metabolism and testicular

function

● Fetal life ○ Cryptorchism: ; Most common congenital condition of testes; one or both testes fail to

descend into scrotum; testis that is not 4 cm or more below the pubic trabecule in an infant

○ Does not interfere with puberty or maintenance of secondary sex characteristics ○ Increased risk of testicular cancer; ○ Untreated – infertility ○ Treat with hormonal therapy or surgery – preferably by age 2

Intra-abdominal testis (10%)

Canalicular testis (20%)

High scrotal testis (40%)

Obstructed testis (30%)

● Neonatal life ○ Temporary inhibition of pituitary-testicular axis → impaired

testicular function at puberty ● Puberty

○ 1. Sexual precocity ■ Sexual development prior to age 9

□ Complete: virilization with spermatogenesis

□ Incomplete: virilization no spermatogenesis

■ Virilizing syndromes □ Hypothalamo-pituitary activity is normal, testosterone level is ↑

♦ Leydig cell tumors

♦ Human chorionic gonadotropin-secreting tumors

♦ Congenital adrenal hyperplasia

■ Premature activation of hypothalamo-pituitary axis □ Idiopathic or CNS tumors

○ 2. Delayed/incomplete puberty ■ See hypothalamic and pituitary diseases with undervirilization and

infertility 343

Infertility in adult life

Hypothalamic-pituitary disorders

with undervirilization with normal virilization

•Congenital isolated gonadotropin deficiency

•Hypogonadotropic hypogonadism (see

Kallman’s syndrome)

•Fertile eunuch syndrome: FSH normal →

normal spermatogenesis; LH↓ testosterone ↓

•Panhypopituitarism

•Hyperprolactinemia

•GnRH receptor, LHß and FSHß mutations

•Adrenal hypoplasia congenita: mutation in DAX1

gene (hypogonadotropic hypogonadism + adrenal

insufficiency), X-linked

•Cushing’s syndrome: high plasma cortison

depresses LH secretion

•Hemochromatosis: iron deposition in testes and

pituitary (no LH response to GnRH)

•Isolated FSH deficiency: no or low FSH, LH

and testosterone normal

•Congenital adrenal hyperplasia (C-17, 21 OH

defect)

•Pharmacologic doses of androgens (anabolic

steroids)

344

Testicular defects – Developmental/structural defects

with undervirilization with normal virilization

•LH receptor inactivating mutation

(psedohermaphroditsm)

•Klinefelter's syndrome (classic form: 47,XXY; mosaic

form: 46,XX/47,XXY)

Small, firm testes, azospermia, gynecomastia, tall

stature (longer lower body segment), elevated

gonadotropin levels, low testosterone, learning

disabilities; taurodontism (abnormal dental pulp)

•XX male (Klinefelter's variant)

Male psychosexual identification, normal height,

no cognitive impairment

Plasma testosterone is low and plasma levels of

estradiol and gonadotropins are high

Male development in absence of Y chromosome

Mosaicism for Y containing cell line

Gain of function mutation for some

autosomal genes

Y chromosome translocation to X

chromosome (~ 80%, often only SRY gene

[mediates testicular development])

•Germinal cell defects; Sertoli-cell only syndrome:

lack of germinal elements; LH usually normal,

FSH high

•FSH receptor inactivating mutation (oligospermia

& normal testosterone level)

•Cryptorchism

•Varicocele – 10-15% in general population

(pampiniform plexus)

•Kartagener’s syndrome: Immotile cilia syndrome

+ situs inversus

345

Acquired testicular defects

with undervirilization with normal virilization

Mumps (viral orchitis)

Trauma

Radiation

Drugs

Spironolacton, ketoconazole and cyproteron: block of testosterone

synthesis (C-17)

Anti-epileptic dugs (phenytoin and carbamazepine): ↓ bioavailable

testosterone

Ethanol: inhibition of testosterone synthesis (3ß-HSD),

spermatogenesis and hypothalamic-pituitary disease

Environmental toxin: lead

Generalized autoimmune diseases & granulomatous diseases

(lepromatous leprosy)

Systemic disease-related testicular defects

Renal failure: 50% of dialysis patients, decrease in plasma

testosterone and increase in plasma FSH and LH

Hepatic disease: cirrhosis – SHBG level ↑, plasma estradiol ↑

(extra glandular conversion of testosterone to estradiol),

testosterone ↓

Sickle cell anemia: due to hypothalamic or testicular defect –

arrested spermatogenesis

Chronic illness: malnutrition, cancer, COPD, cystic fibrosis

Hereditary androgen resistance (LH, testosterone ↑)

Point mutations in androgen receptor

Mycoplasma infection

Radiation

Drugs: alkylating agents

Environmental toxins: ethylene glycol,

cadmium, lead

Autoimmunity

Antibodies to the basement membrane

of seminiferous tubules or to sperms

Anti-sperm antibodies – prevent

penetration of cervical mucus

Systemic disease-related testicular defects

Acute febrile illness

Celiac disease

Spinal cord injury

Acquired androgen resistance

Increased CAG sequence in androgen

receptor

Sperm transport defects

Obstruction of epididymis or vas

deferens: cystic fibrosis, vasectomy

346

347

Estrogen excess – gynecomastia

● Physiologic gynecomastia ○ Newborn, adolescent, aging

● Pathologic gynecomastia ○ Relative estrogen excess (decrease in

testosterone) ■ Congenital defects

□ Congenital anorchia

□ Klinefelter’s syndrome

□ Reinfenstein’s syndrome (partial deficiency of the

androgen receptors)

□ Defects in testosterone synthesis: 3ß-HSD and 17ß-

HSD deficiency

■ Secondary testicular failure: viral orchitis, trauma,

castration, renal failure etc

348

○ Increased estrogen production ■ Increased testicular estrogen secretion: testicular tumors, hCG

producing tumors (bronchogenic carcinoma)

■ Increased substrate for extraglandular aromatase □ Adrenal (C-21 OH defect), liver diseases; starvation, thyrotoxicosis

■ Increased extraglandular aromatase

○ Drugs that ■ Act like estrogens (diethyl stilbestrol, cosmetics, phytoestrogens)

■ Enhance endogenous estrogen production (gonadotropins)

■ Inhibit testosterone synthesis (see before)

■ Act by unknown mechanism (e.g. marihuana, heroin)

● Idiopathic gynecomastia

349

Impairment of estrogen formation and action

● Aromatase deficiency ○ Loss of function mutation (C-19 gene)

● Estrogen receptor a-subunit deficiency

● Common features of estrogen deficiency ○ Tall stature, no growth spurt at puberty, rather continuous growth

without epiphyseal closure

ADH

Dehydration Lowers blood volume and pressure

Increased water retention

Increased vasoconstriction leading to higher blood pressure

Reduced urine volume

Osmotic concentration

of blood increases

ADH synthesized by neurosecretory cells in hypothalamus

ADH released from posterior pituitary into blood

Osmoreceptors Negative feedback Negative

feedback

350

Vasopressin: physiology & pathophysiology

● Osmotic stimulation ○ Due to increase in plasma

osmotic concentration

● Non-osmotic stimulation ○ Baroreceptors: cardio-

pulmonary, sino-aortic

○ Intracardial, intra-aortic

pressure ↓

○ Angiotensin II (AT-II)

○ Central a2 adrenergic, opiate,

dopamine receptor

351

352

Wateracquisition

Oropharyngealreflex

Thirst

Angiotensin II

Baroreceptor

10% decrease incirculating volume

Waterconservation

Antidiuresis

ADH release

CNSosmoreceptor

2% increaseECF osmolality

Circulating volume incr.

ANP incr.

PGE2incr

ET-1

Diseases with non-

osmotic

ADH release

1. Decrease in

circulating volume:

bleeding, GI and

renal fluid loss

2. After surgery: due to

pain, hypotension,

hypoxia and

anesthesia

3. Edema formation:

cardiac, liver,

pregnancy

Vasopressin: clinical uses

● Diagnostic use: To differentiate central and nephrogenic DI. ○ One hour after treatment, urine osmolality should increase > 50

% if cause is AVP deficiency

● V1-mediated contraction of GI smooth muscle ■ To treat post-operative ileus

■ To dispel intestinal gas before abdominal imaging

■ Emergency treatment of bleeding esophageal varices (varicose

veins)

■ Acute hemorrhagic gastritis

● V2 antagonist: to treat edema

353

354

Diabetes insipidus

● Common features of diabetes insipidus ○ Decreased reabsorption of free water in kidney → isovolemic

hyperosmotic hypernatremia (plasma osmolality > 295

mOmsol/kg)

○ Excretion of large volumes of dilute (< 200 mOmsol/kg) urine

(polyuria, nocturia)

○ Stimulation of thirst (polydipsia)

355

● 1. Pituitary / Central diabetes insipidus (CDI): defect in

vasopressin production and/or release ○ 50 % of cases are idiopathic: DI becomes symptomatic only with

an 80-85 % reduction of AVP cells

○ Congenital central diabetes insipidus (CDI) ■ Autosomal dominant – caused by mutation in vasopressin-

neurophysin II gene

■ Autosomal recessive – Wolfram syndrome: CDI, DM, optic atrophy

and deafness

○ Acquired central diabetes insipidus ■ Trauma, cysts, histiocytosis, granuloma (tuberculosis, sarcoidosis),

aneurysms, meningitis, encephalitis, Guillain-Barré syndrome

■ Metastatic tumor from breast cancer, craniopharyngioma,

pinealoma

356

● 2. Nephrogenic DI – the renal collecting duct does not respond

appropriately to ADH ○ Congenital nephrogenic DI

■ Autosomal recessive form of NDI is caused by mutation in AQP2

■ X-linked NDI: V2 receptor mutation – cyclic AMP is not generated in

response to AVP

○ Acquired nephrogenic DI: more common but less severe ■ Diseases

□ Chronic renal failure, hypercalcemia and hypokalemia

□ Sickle cell anemia or trait (medullary vascular injury)

■ Excessive water intake or primary polydipsia (decreased medullary

tonicity)

■ Severe protein restriction (decreased medullary urea & tonicity)

● 3. Gestational DI ○ Vasopressinase produced by placenta inactivates circulating

vasopressin

○ Treatment: desmopressin (DDAVP – resistant to vasopressinase)

357

>90%

Congenital nephrogenic diabetes insipidus Physiological conditions

358

Syndrome of inappropriate ADH secretion

(SIADH)

● Causes of SIADH ○ Malignancies (Schwartz-Bartter syndrome)

■ Small-cell lung carcinoma, duodenum, pancreas and olfactory

neuroblastoma – ectopic ADH production

○ Pulmonary disease ■ Pneumocystis jirovecii – HIV + CNS infections and malignancies

○ CNS disorders ■ Tumors, infections, trauma – releasing excess ADH

359

● Impaired water excretion in the presence of hyponatremia

(isovolemic, hypotonic) and hypoosmolality. Defective

osmoregulation → a urinary concentration inappropriately high

(↑ ADH → excessive reabsorption of free water) to the degree

of hypoosmolality ○ The commonest cause of hyponatremia in hospital patients with

oliguria, and high specific gravity (with inability to dilute it)

○ Hypoosmolality may produce lethargy, anorexia, nausea and

vomiting, muscle cramps; may lead to coma, convulsions, and

death

● Therapy ○ Restriction of fluid intake, inhibition of ADH

360

Resetting of the osmostat

● Functional disease ○ In one-third of SIADH patients

○ Chronic diseases: lung tuberculosis, hepatic cirrhosis,

malnutrition, pregnancy

● Osmolality is kept at 250 mOsmol/kg and serum Na at 120

mmol/l

● Features ○ Upon exogenous water load: Urine dilution is appropriate to water

load; Low Na concentration is maintained

○ In water depletion: concentrated urine; Low Na concentration is

maintained

Oxytocin (OT)

● Action and mechanism of action: specific G protein-coupled receptors ○ frequency and force of uterine smooth muscle contraction during parturition

○ contraction of mammary myoepithelial cells and milk ejection

● Clinical uses ○ OT test for uteroplacental insufficiency: indicates whether placental reserve is

sufficient for continuation of a high-risk pregnancy (Fetal heart rate used as a

measure of distress)

○ Induction of term labor

○ Control of postpartum bleeding

○ For increasing milk ejection: administered as a nasal spray 2 to 3 minutes

before breast-feeding

● Other effects of OT ○ OT attenuates endocrine and autonomic responses to stress, mediator for the

stress-protective effects of social support, attenuate amygdala reactivity to

social stimuli and reduce brainstem activity to autonomic arousal and

enhanced readiness to show social approach behavior and empathy 361

362

Afferent neurons carry information from sensory

receptors to the spinal chord

Efferent neurons relay the message to

the paraventricular nucleus (PVN) within

the hypothalamus

Hypothalamic neurons release

oxytocin, which travels down the

axon to the posterior

hypophysis

The posterior hypophysis

releases oxytocin into the

bloodstream

Oxytocin travels to target cells

with receptors specific to this

hormone

363

Parathyroid gland

364

Parathyroid glands and Ca homeostasis

● Main role is to regulate Ca, Mg and phosphate (Pi)

● Parathyroid hormone (PTH)

● Produced by parathyroid chief cells in response to low iCa++

● PTH → Type 1 PTH receptor (PTH1R) → activation of Gsα →

cAMP↑

○ Stimulates renal Ca++ & Mg++ absorption in distal tubules and

thick ascending limb and decreases the reabsorption of

phosphate PO43- in the proximal tubules

○ Stimulates proximal renal tubular conversion of 25-(OH)D3 to

1,25-(OH)2D3 which increases intestinal Ca++ and phosphate

absorption

○ Stimulates osteoclastic resorption of bone

365

Ca Phosphate PTH anticalciuric effect

PTH phosphaturic effect

Calcitonin

● Non-essential hormone.

Patients with total

thyroidectomy maintain normal

Ca++ concentrations

● Produced by parafollicular C

cells of thyroid gland in

response to increased iCa++

● Inhibit osteoclastic resorption of

bone and Ca resorption from

intestine

● Inhibit renal Ca++ and PO43-

reabsorption

Vitamin D

● Sources ○ Food – Vitamin D2

○ UV light mediated cholesterol

metabolism – D3

● Metabolism ○ D2 and D3 are converted to

25(OH)D3 by the liver

○ 25(OH)D3 is converted to

1,25(OH)2D3 by α hydroxylase

upon PTH stimulus in the proximal

tubulus

● Function ○ Stimulation of osteoblasts

○ Increases GI absorption of dietary

Ca++ and phosphate

366

367

● Calcium (2.1-2.6 mmol/l; iCa++ 1.14-1.2 mmol/l) ○ Required for muscle contraction, intracellular messenger

systems, cardiac repolarization.

○ Exists in free and bound states ■ Free (50% - biologically active) iCa++

■ Albumin bound (40% total Ca)

■ Complexes with anions: bicarbonate, lactate, sulphate, phosphate

and citrate (10% total Ca)

○ Concentration of iCa++ mediated by ■ Parathyroid gland, parafollicular C cells, kidney, bone

■ Ca level should be corrected in hypoalbuminemia and acidosis

368

Hypocalcaemia (< 2.1 mmol/l; iCa2+ <1.14 mmol/l)

● I. Lack/ineffective PTH ○ 1. Hypoparathyroidism

■ Idiopathic (familial or autoimmune disorders)

■ Surgical removal of the gland

■ Infiltrative diseases (amyloidosis)

■ Congenital lack of the gland: see DiGeorge syndrome

○ 2. Defects in PTH1R (chondrodysplasia) ■ Low PTH, however in activating PTH1R mutation plasma Ca can

be high

369

○ 3. PTH resistance or pseudohypoparathyroidism: inactivating

mutation of Gsα protein encoding gene; end-organ insensitivity to

PTH ■ Low Ca++, and increased phosphate and PTH levels

■ There are several forms of pseudohypoparathyroidism: one is

associated with Albright hereditary osteodystrophy (short stature,

round face, short neck, short metacarpals and metatarsals) and

resistance to TSH, GHRH and gonadotropins

○ 4. Hypomagnesemia (low Ca and K level) ■ Mg is essential for normal PTH function

■ Decreased PTH secretion, diminished response to PTH

● II. Inappropriate vitamin D metabolism ○ Genetic defects of vitamin D metabolism: vitamin D dependent

rickets (rachitis) ■ Type 1: pseudo vitamin D deficient rickets: Inactivating mutation of

1-OH gene

■ Type 2: vitamin D resistance: Vitamin D receptor gene defect

○ Malnutrition: vitamin D deficiency

○ Malabsorption: hepatobiliary diseases

○ Kidney diseases ■ Chronic renal insufficiency: ↓ in renal mass ↓ 1,25-(OH)2D3 → →

secondary hyperparathyroidism

■ Nephrotic syndrome (loss of vitamin D binding protein)

370

371

● III. Increased Ca complexation ○ Pancreatitis: pancreatic lipase – degradation of retroperitoneal

omental fat (Ca and Mg soap)

○ Oxalic acid / fluoride / citrate (blood products) poisoning

○ Iatrogenic: after ACTH, steroid, EDTA and furosemide

administration

○ „Hungry bone” syndrome ■ Rapid bone mineralization after parathyroid surgery of osteitis

fibrosa cystica (von-Recklinghausen’s disease), or

■ vitamin D administration in rickets

○ Increased plasma phosphorus level ■ Crush syndrome, trauma, renal failure

■ Phosphate-containing laxatives, infusions

Symptoms of hypocalcaemia

● Neuromuscular irritability: Paraesthesiae of the distal extremities and

circumoral area; muscle cramps, laryngospasm, tetany and seizures ■ Erb sign: Increased electric excitability of the muscles to the galvanic

current, and frequently to the faradic, in tetany

■ Chvostek sign: Facial twitch elicited by tapping on the facial nerve just

below the zygomatic bone with the patient’s mouth slightly open

■ Trousseau sign: Brachial artery occlusion with a sphygmomanometer cuff

inflated above the systolic blood pressure for 3 min: Wrist and

metacarpophalangeal joint flexion, hyperextended fingers, and flexion of

the thumb on to the palm

■ Peroneal sign: dorsiflexion and abduction of the foot on tapping the

peroneal nerve on the lateral surface of the fibula just before the knee

○ Cardiac manifestations – prolonged QT interval which may progress to

ventricular fibrillation or heart block

372

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Hypercalcaemia (> 2.6 mmol/l; iCa++ >1.2 mmol/l)

● I. Excess PTH production ○ 1. Primary hyperparathyroidism – autonomous parathyroid

hyperfunction ■ Parathyroid adenoma

□ 80% of cases of hyperparathyroidism

□ Stepwise acquired mutations of MEN1 (inactivating) and cyclin D1

(activating) genes

■ Type 1 Multiple Endocrine Neoplasia (MEN1) □ Sequential inactivation of both copies of MEN1 gene (tumor

suppressor)

■ Familial hypocalciuric hypercalcemia □ Monoallelic inactivation of Ca-sensing receptor genes (decreases the

Ca sensing by parathyroid cells and renal tubules)

374

■ Neonatal severe primary hyperparathyroidism

□ Biallelic inactivation of Ca-sensing receptor genes (decreases

the Ca sensing by parathyroid cells and renal tubules) often

lethal

■ Multiple Endocrine Neoplasia Type 2a (MEN 2a)

□ Activating mutation of the RET protoncogene

○ 2. Tertiary hyperparathyroidism ■ Increased PTH response persists (to renal and intestinal

hypocalcaemia)

■ Adenoma formation in patients with secondary

hyperparathyroidism due to parathyroid hyperplasia

375

● II. Pseudo-hyperparathyroidism ○ Neoplasia without skeletal involvement (circulating tumor-derived

agents with bone-resorbing capacity

○ Immunologically distinct form PTH; e.g. EGF, PDGF causes

prostaglandin dependent bone resorption)

○ PTH level is not high

● III. Excess 1,25(OH)2D3

○ Vitamin D intoxication

○ Boeck sarcoidosis ■ bone reabsorption and intestinal absorption) and sensitivity to

vitamin D (conversion of 25(OH)D3 to 1,25(OH)2D3

○ Neoplastic production of 1,25(OH)2D3 – lymphoma

376

● IV. Increased bone reabsorption ○ Metastatic tumor

■ Breast, colon, prostate

○ Neoplasia with skeletal involvement ■ Circulating, tumor-secreted (PTH-related peptide, 1,25(OH)2D3) –

lung, renal cc.

■ Locally acting, non-circulating, tumor-secreted factors (osteoclast

activating factor, IL-1, PG-s) – in myeloma, lymphoma

○ Overdose of vitamin A

○ Immobilization: bed rest over 4 weeks

● V. Endocrine disorders ○ Hyperthyroidism and pheochromocytoma (↑ bone resorption)

○ Adrenal insufficiency (nonionic compartment of Ca ↑)

○ Acromegaly

● VI. Increased intestinal absorption of Ca ○ Milk-alkali syndrome (Burnett’s syndrome) [rare]

■ Alkali is known to exert hypocalciuric effect on distal nephron

■ Increased Ca reabsorption from milk

○ Excess Ca or Ca-carbonate intake to prevent osteoporosis

[frequent]

○ Vitamin D intoxication

● VII. Decreased renal excretion of Ca ○ Familial hypocalciuric hypercalcemia (see earlier)

● VIII. Impaired bone formation and incorporation of Ca ○ Aluminum intoxication

○ Adynamic (low turnover) bone diseases (chronic renal failure)

○ Administration of corticosteroids 377

378

Symptoms of hypercalcaemia

● Neurological manifestations ○ Mild drowsiness, progressing to weakness, depression, lethargy,

stupor, and coma

● Gastrointestinal symptoms ○ Constipation, nausea, vomiting, anorexia, and peptic ulcer

disease

○ Recurrent pancreatitis (Ca deposition and ductal obstruction)

● Renal symptoms ○ Nephrogenic diabetes insipidus - polyuria leading to ECF volume

depletion and a reduction in the glomerular filtration rate (GFR),

which may lead to a further increase in Ca concentration.

○ Nephrolithiasis, nephrocalcinosis ■ Ca kidney stones, metastatic calcification of glomerulus

379

● Cardiac symptoms ○ Potentiating digitalis toxicity

○ Arrhythmia

○ Tachycardia

○ Decreased Q-T interval

● Osteitis fibrosis cystica (von-Recklinghausen disease) ○ Lytic bone lesions caused by hyperparathyroidism

○ Resorption of the distal phalanges characteristically occurs.

● Metastatic calcification ○ Calcification of soft tissues resulting from hypercalcemia or

hyperphosphatemia

● Easy to remember: signs & symptoms of hypercalcaemia ○ Bones (osteitis fibrosa cystica, osteoporosis, rickets)

○ Stones (renal stones)

○ Groans (constipation, peptic ulcer)

○ Moans (lethargy, depression, confusion)

380

RR=71/min, SR, Normal axis

PR=0.22 sec, RR=0.84 sec, √RR=0.92 sec

RR=79/min, SR, Normal axis

PR=0.16 sec

RR=115/min, ST, -30o

PR=0.12 sec

QTc 0.48/0.92=0.52

381

Multiple endocrine neoplasia: MEN Familial

hyperparathyroidism

● Multiple Endocrine Neoplasia (MEN) are autosomal dominant

syndromes characterized by overproduction of a variety of hormonal

substances

● MEN 1(Wermer’s syndrome) ○ Genetic defect on chromosome 11. defect in MEN1 gene – which is

likely a tumor suppressor gene (MEN1 encodes menin protein which

suppresses tumor growth) ■ 1. Parathyroid hyperplasia or adenoma (95%)

■ 2. Pancreatic islet cell tumors (75%) with excessive secretion of □ Gastrin → peptic ulcers (Zollinger-Ellison syndrome)

□ Insulin → hypoglycemia

□ Serotonin → carcinoid syndrome

□ VIP → watery diarrhea

■ 3. Pituitary adenoma (66%); □ Prolactinoma, but GH & ACTH producing adenomas

382

● MEN 2a (Sipple’s syndrome)

○ Inherited mutation in the RET proto oncogene on chromosome

10*.

■ 1. C cell hyperplasia or medullary thyroid carcinoma (100%)

■ 2. Pheochromocytoma (50%), often bilateral and may arise in the

extra-adrenal paraganglia

■ 3. Parathyroid hyperplasia or adenoma (25%)

● MEN 2b (Gorlin’s syndrome)

○ Inherited mutation in the RET protooncogene on chromosome

10*, different from that seen in MEN 2a

○ Neoplasms are as in MEN 2a and mucosal neuroma syndrome:

■ Ganglioneuromas of the skin, eyes and mucous membranes of the

mouth, GI tract, respiratory tract & bladder (100%)

■ Marfanoid body habitus (65%)

*due to RET mutation early thyroidectomy